Today, researcher Victor Bjoerk talks us through his latest published paper, in which he describes a neurodegenerative disease that affects the circadian clock.
A circadian clock disease
With aging, the brain runs into multiple issues; however, some are more serious than others and cause disease symptoms throughout the body. While aging of some brain areas, such as the substantia nigra, leads to well-known diseases such as Parkinson’s, other areas have not received disease classifications.
In my new paper, I came up with the idea of labeling the aging damage of another brain region, the suprachiasmatic nucleus (SCN), as a disease [1]. The SCN is a small cluster of about 10,000 neurons that regulate sleep and circadian rhythms throughout the whole body. This new disease is called Circadian Clock Neuronal Senile Atrophy (CIRCLONSA) syndrome, and it is important to classify it as a disease so that efforts to defeat it can receive proper research focus and funding for biotechnological entrepreneurship.
The suprachiasmatic nucleus (SCN) in the brain is the master regulator of the circadian clocks throughout the human body. With increasing age the circadian clock in humans and other mammals becomes increasingly disorganized leading to a large number of more or less well categorized problems. While a lot of aging research has focused on the peripheral clocks in tissues across organisms, it remains a paramount task to quantify aging of the most important master clock, the human SCN. Furthermore, a pipeline needs to be developed with therapies to mitigate the systemic cellular circadian dysfunction in the elderly and ultimately repair and reverse aging of the SCN itself. A disease classification for the aging SCN, Circadian Clock Neuronal Senile Atrophy, (CIRCLONSA syndrome), would improve research funding and goal-oriented biotechnological entrepreneurship.
Aging of the SCN contributes to the problem of elderly getting good sleep since it misaligns the signals to the brain’s sleep center, leading to waking episodes during the night and low quality of sleep in the elderly. However, there are many more issues; for example, cell division across the whole body is controlled by circadian rhythms, which should contribute to an increased risk for cancer with old age due to cells receiving the wrong signals of when to divide. An aging SCN also contributes to sarcopenia and generalized metabolic dysfunction.
It is well known that shift workers are more prone to many diseases, and, for this reason, it is a good idea to keep healthy habits when it comes to getting good sleep during regular, daylight hours. However, aging makes the SCN decline, which means that old people, in many ways, get the same metabolic problems as shift workers, which is on top of other aging damage.
While research has been going on in this area for several decades, there has been no attempt to address this by developing a pipeline of therapies. However, there exists proof of principle that the SCN is very important, as transplantation of young SCN tissue to aged hamsters led to a life extension of 12% in a study performed in the 1990s.
Several things inside the SCN make it deteriorate with age; for example, ion signaling is disturbed due to membrane changes in the aging cells. Also, they are filled with lipofuscin, which is a mixture of lipids and fats that take up space inside the aging brain. The different neurons inside the SCN have specialized functions, with different neuropeptides responsible for synaptic transmission; when this ability is lost with age, it produces an erratic circadian rhythm.
What can we do to address this condition?
More drugs affecting circadian hormones might be developed to help improve the general health of the elderly with everything from sleep to cancer risk. There are already some relevant pharmaceutical compounds, such as CLK8, which improves circadian oscillations [2], and SR9009. Interestingly, SR9009 is listed as being a potential doping compound, since it increases muscle mass. It also improves metabolism through increasing mitochondrial count through interaction with the circadian clock [3].
I also propose using a brain pump to take over the functions of the aging SCN to restore the circadian signaling in the body to youthful levels; since the SCN communicates with many brain regions, it is important that any intervention can generate effects within the brain.
What would constitute a solution to the problem would be a full repair approach that repopulates the lost neurons and/or reverses damage to the neurons themselves.
When trying to cure age-related diseases, some problems are going to be more important than others to address in order to achieve a prolonged healthspan/lifespan. In this paper, I argue that CIRCLONSA should be seen as a major disease affecting the whole body; the restoration of this brain clock would improve many different issues at once in the aging body.
Literature
[1] Björk V. Aging of the Suprachiasmatic Nucleus, CIRCLONSA syndrome, implications for regenerative medicine and restoration of the master body clock. Rejuvenation Res. 2021 Feb 11. doi: 10.1089/rej.2020.2388. Epub ahead of print. PMID: 33573456.
[2] Doruk YU, Yarparvar D, Akyel YK, et al. A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude. J Biol Chem. 2020;295(11):3518-3531. doi:10.1074/jbc.RA119.011332
[3] Solt LA, Wang Y, Banerjee S, et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature. 2012;485(7396):62-68. Published 2012 Mar 29. doi:10.1038/nature11030
